Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3Hjalen-dronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 itm away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone.In vitro alendronate bound to bone particles with a Kd of -1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 X 10-3 fmol/Mm2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts. (J.
Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1–3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4–7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
Preaxial polydactyly (PPD) is a common limb malformation in human.A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch (Ssq). The genetic lesions in both lie within the same respective intron of the LMBR1͞Lmbr1 gene, which resides Ϸ1 Mb away from Shh. Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh. This regulator is most likely the target for generating PPD mutations in human. )] is one of the most frequently observed human congenital limb malformations. Sporadic cases of PPD have been described, but most show an autosomal-dominant mode of inheritance. The limb-specific phenotype varies markedly within families, ranging from a simple addition of a phalanx in triphalangeal thumb to whole digit duplications and tibial aplasia. Using several large families, a PPD locus was mapped to a 450-kb region on chromosome 7q36, and all families described so far are linked to this locus (1-5). Recent reports suggest that PPD constitutes one aspect of a complex disease locus. Acheiropodia (6), complex polysyndactyly (CPS) (7), and acropectoral syndrome (8) are all distinct, limb-specific disorders that map to this region, suggesting that elements essential for limb development are located in this locus. Sasquatch (Ssq) is a mouse mutation that arose through a transgenic insertion (9). The mutation is semidominant, resulting in supernumerary preaxial (anterior) digits on the hindfeet in the heterozygotes. In homozygotes both fore-and hindlimbs show additional preaxial digits, and in some cases the long bones are shortened such that the limbs appear twisted. The insertion site responsible for the Ssq phenotype is physically linked to within Ϸ1 Mb of Shh.Here, we show that Ssq maps to the region on mouse chromosome 5 that corresponds to the human PPD locus. We identify mutations in a PPD patient and in the Ssq mouse. The PPD patient carries a de novo chromosomal translocation. Isolation of the PPD translocation breakpoint and the Ssq transgene insertion site revealed a similar location for these genetic disruptions within the Lmbr1 gene. We provide genetic analysis that shows that the Ssq mutation is not acting locally but in fact interrupts a long-range cis-acting regulator. This regulator operates on Shh residing 1.8 cM away, corresponding to a physical distance of Ϸ1 Mb. Consequently, disruption of Shh regulation is most likely the basis for PPD in humans. Materials and MethodsPatient Material. The translocation patient was clinically examined, and a member of her family was interviewed for family history at the Niigata University Hospital. All studies were approved by the local ethics committee. A member of the family gave written informed consent on behalf of the patient. The PPD families used in this study are...
IntroductionIn 1998, the first Japanese practice guidelines on osteoporosis was published. It has been updated several times, with the most recent being the full-scale 2011 edition and its abridged edition. The present guidelines provide information for the managements of primary osteoporosis in postmenopausal women and men over 50 years old, a summary of the evidence for the treatment of secondary osteoporosis, and a summary of the evidence for the prevention of osteoporosis in younger people.MethodThe present Executive Summary is primarily based on the content of the 2011 Japanese abridged edition. One of the key changes is revision of the criteria for initiation of pharmacological treatment, along with an introduction of the fracture risk factors used in FRAX®. Key figures and tables were selected from the Japanese abridged edition and a reference list was added.Result and conclusionsThe essential points of the Japanese practice guidelines on osteoporosis were translated into English for the first time. It is hoped that the content of the guidelines becomes known throughout the world.
PGE, and PGE2 are potent stimulators of bone formation. Osteogenesis is strongly dependent on angiogenesis. Vascular endothelial growth factor (VEGF), a secreted endothelial cellspecific mitogen, has been implicated in physiological and pathological angiogenesis. The aim of this study was to examine the possible role of VEGF in PG stimulation of bone formation. We found that in rat calvaria-derived osteoblast-enriched cells and in the osteoblastic RCT-3 cell line PGE2 and El increased VEGF mRNA and protein levels. The increased expression of VEGF mRNA produced by PGE2 was rapid (maximal at 1 h), transient (declined by 3 h), potentiated by cycloheximide, and abolished by actinomycin D. PGE2 had no effect on VEGF mRNA stability, suggesting transcriptional regulation ofVEGF expression by PGE2. Rp-cAMP, a cAMP antagonist, suppressed VEGF mRNA induced by PGE2, indicating cAMP mediation. The upregulation of VEGF expression by PGE2 in the preosteoblastic RCT-1 cells was potentiated by treatment with retinoic acid, which induces the differentiation of these cells. The upregulation of VEGF mRNA by PGE2 was inhibited by dexamethasone treatment. In addition, Northern blot analysis showed that VEGF mRNA is expressed in adult rat tibia. In summary, we documented, for the first time, the expression of VEGF in osteoblasts and in bone tissue. Stimulation of VEGF expression by PGs and its suppression by glucocorticoids, which, respectively, stimulate and suppress bone formation, strongly implicate the involvement of VEGF in bone metabolism. (J. Clin. Invest. 1994.93:2490-2496
Long-term results are reported in 23 patients and short-term results in 30 patients presenting with bone tumors treated by curettage or resection followed by implantation of hydroxyapatite (HA) or highly purified beta-tricalcium phosphate (-TCP), respectively. Mean follow-up was 97 and 26 months in cases involving HA implantation and -TCP implantation, respectively. Radiographs revealed HA incorporation into host bone in all but two cases; moreover, no obvious evidence of HA biodegradation was observed. A single patient exhibited late deformity following implantation of HA. All grafted -TCP was, at least partially, absorbed and replaced by newly formed bone. The mean period required for the disappearance of radiolucent zones between the ceramics and host bone was 17 weeks in HA and 9.7 weeks in -TCP. Highly purified -TCP appears to be advantageous relative to HA for surgical intervention in bone tumors consequent to the nature of remodeling and superior osteoconductivity.
In 1995, the Japanese Society for Bone and Mineral Metabolism (now the Japanese Society for Bone and Mineral Research) established the Osteoporosis Diagnostic Criteria Review Committee. Following discussion held at the 13th scientific meeting of the Society in 1996, the Committee, with the consensus of its members, proposed diagnostic criteria for primary osteoporosis. The Committee revised those criteria in 1998 and again in 2000. The Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis aimed at obtaining international consistency and made a revised edition based on the new findings in 2012.
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